3-alkoxy-or 3-aryloxy-2-(diaryl-hydroxy)-methyl-propylamines

ABSTRACT

IN WHICH Ar and Ar&#39;&#39;, which may be the same or different, are unsubstituted or substituted aryl groups, R is an aliphatic, aryl or arylaliphatic group, and A is a secondary or tertiary amino group, or an acid addition salt thereof. The compound has coronarodilating properties and central nervous system activity.   A 3-alkoxy- or 3-aryloxy-2-(diaryl-hydroxy)-methyl-propylamine of the formula

United States Patent [191 Mauvernay et al.

[ June 18, 1974 3-ALKOXY-0R SARYDOXY-Z-(DIARYL-HYDROXW- ME'IHYL-PROPYLAMINES [75] Inventors: Roland Yves Mauvernay, Riom;

Norbert Busch, Loubeyrat; Jacques Simond, Chamalieres; Jacques Moleyre, Nozac, all of France [73] Assignee: Centre Europeen De Recherches Mauvernay C.E.R.M.

[22] Filed: Mar. 28, 1972 [21] Appl. No.: 238,969

Related US. Application Data [62] Division of Ser. No. 447, Jan. 2, 1970, Pat. No.

[30] Foreign Application Priority Data Jan. 3, 1969 Great Britain 452/69 [52] US. CI.260/247.7 C, 260/247.7 A, 260/293.83, 260/326.5 R, 260/326.5 M

[51] Int. Cl C07d 87/32 [58] Field of Search. 260/247.7 A, 247.7 C, 293.83, 260/326.5 R, 326.5 M

[56] References Cited UNITED STATES PATENTS 2,881,174 4/1959 Wright 260/570 2,881.2I6 4/1959 Wright 260/570 3,723,476 3/1973 Nakanishi et al 260/347.7

OTHER PUBLICATIONS Wright, Chem. Abstracts 55: I 34056( I961 Primary E.raminer-G. Thomas Todd Attorney, Agent, or FirmEric H. Waters ABSTRACT A 3-alkoxyor 3-aryloxy-2-(diaryl-hydroxy)-methylpropylamine of the formula Ar OH 1 Claim, N0 Drawings 3-ALKOXY-OR 3-ARYLOXY-2-(DIARYLHYDROXY )-METHYL- PROPYLAMINES CROSS-RELATED APPLICATION This application is a division of our earlier application Ser. No. 447, filed Jan. 2, i970, and issued July 1 l, 1972 as U.S. Pat. No. 3,676,496 claiming the priority of our earlier application filed in Great Britain on Jan. 3, 1969. i

This invention relates to certain novel substituted propylamines.

We have found that 3-alkoxyor 3-aryloxy-2-(diarylhydroxy) methyl-propylamines of the formula Ar OH At CH-CHa-A Hr-oli (I) in which Ar and Ar, which may be the same or differcm, are unsubstituted or substituted aryl groups, R is an aliphatic, aryl or arylaliphatic group, and A is a secondary or tertiary amino group, and their acid addition salts, have remarkable coronarodilating properties and central nervous system activity, and certain of them have bactericidal and anti-virus activity. These compounds are novel and constitute one aspect of the present invention.

it is known that 2-hydroxy-3-alkoxy (and 3-aryloxy)- propylamines have a blocking effect on B-adrenergic receptors and a number of patents refer to these compounds. For example, Belgian Pat. No. 669 40], Dutch Pat. Nos. 64/09883, 65/04268, 66/00177, 66/05692 and 66/08099, French Pat. No. 5190M and U.S. Pat.

No. 3 30 9 40 describe compounds of the formula:

Hill) CH-CHs-A .li'f fn' will in which A is a secondary or tertiary amino group and R is an unsubstituted or substituted aryl group, and Belgian Pat. No. 669,789 describes compounds of formula ll in which R is an aliphatic group.

in U.S. Pat. applications Ser. NO. 749 277 (Aug. 1, 1968) and 842 388 (July 16, I969) Compounds are described following the formula X (EH-CHr-A HrH 42a in which A and R have the above-stated meanings and X is OCOAr or NHCO--Ar, where Ar has the above-stated meaning. While in the compounds of formula ll described in the above-mentioned patent specifications, the ,8 blocking effects are preponderant, such effects are substantially non-existant in the compounds of formula III, and the latter have, on the other hand. remarkable anti-arrythmic and coronaro-dilating effects.

and in South African Patent 67/5430 which describes compounds of the formula:

in the above formulae R, Ar and Ar have the abovestated meanings.

The compounds of formula I can be prepared from known compounds of formula II by a two stage process. In the first stage, chlorine is substituted for the hydroxyl group on the carbon atom in the 2- position of the compound of formula [I by the action of thionyl chloride, preferably in chloroform. In the second stage, the 3-alkoxy (or 3-aryloxy)-2-chloro-propylamine prepared in the first stage is condensed with a bis-aromatic ketone (containing unsubstituted or substituted aryl groups corresponding to the desired values of Ar and Ar) in the presence of sodium in liquid ammonia to give the desired compound. The reactions may be illustratgd s follows:

, only:

EXAMPLE.

First stage: preparation of N,N-diethyl-(3-isobutoxy-2- hlqrqmmpy ami 5 g of sodium were rapidly dissolved in 300 ml liquid ammonia. 18.2 g benzophenone (().I M) dissolved in anhydrous ether were then added. The reaction was allowed to continue for 15 minutes and 22.2 g of the pre- 180 g of lhiohyl chloride in ml anhydrous C viously prepared halogen derivative were added to the added to a 50mm)" of 2 l 7 g ofNtN'dlethyl resulting mauve solution. The color changed slowly to (3-1sobut0xy-2-hydroxy)-propylamme in 400 ml anhyorange ye|]0w drous G Q-' Wlth Shmhg and While the temperature After continuing the reaction for 4 hours, ll g of was mamtamefi below 5 NH CI was added and the NH formed was allowed to After the thlohyl Chlorlde had been added, the evaporate. The residue was dissolved in water and ture was heated for a further 4 hours under reflux. The ethen Aft d m i h h l phase was Solvent and the excess SOClz were evaporated Off and tracted with an approx. 4N HCl solution. The aqueous p h was Poured t0 crushed ice and made solution was then made alkaline with 40% NaOH and kahhe with 33 Percent aqueous NaOH; The Product the organic product was extracted with ether. was extracted with ether, the extract dried over anhy- Af th ether had been evaporated, the residue as drous Na SQ the ether was evaporated off, and the di l d i thyl acetate and ethanol saturated with resldue d'snhed Vacuo to give 204 g of the above" HCl was added in sufficient quantity to obtain the hynamed product. droch|oride b 2 mm Hg) 200 1.4390; Yield: 86 Arlialysis of the product obtained gave the following percent. Second stage: preparation of N,N-diethyl-[ 3 isobutoxy- Calculmd mind 2-(diphenyl-hydroxy)-methyll-propylamine. m 71.02 70.56 M.P.= 135C m. 8.63 8.2! M 400.02 n v g Na 3.45 3.45 Yield 60% C1 ilH-CH:N(C,H;); cinmoo A similar meth od was used to prepare compounds of formula I in which the substituents Ar and Ar are C H OH phenyl groups and the substituents R and A have the meanings given in Table l hereinafter. Table I also gives the melting point of each compound and the results of 00115 CH-CHT'MCFHDI analytical tests. Compound No. l was the product pre- H -O-CH -CHMJEO: pared in the preceding example.

TA'BIJ'E I" Hydrochloride HCl Compound M.P. calcu- H01 No. A C.) lated found 1 1 CH3 0&1, 135 0.01 9.00

CH-CHr- N- cHi CIHE a 154 s 44 s so CH-GHz-OHe- 3 Bameasabove \N 150 8.75 8.90

4 do 135 8.34 we 5 ..do 02H;

CH--CH2- C 0 0113- can 10.01 0. 08

02H: 10 CH3' "0.73 0165' i TABLE 1-Continued r M Hydrochloride HC 1 Compound M.P. calcu- HCI N R A C.) lated found 12I...'...'...."o,n,- 120 9.72" 6556 1a ozrn- 130 9.36 9.38

14 CzHr- 01H; 162 9.72 9.59

16 Sameasabove Oils 142 8.57 8.70

18 CH CH; 192 10.85 10.70

l Fumarate 130. b Fumarlc acid, calculated 23.3. a Fumarlc acid, found 23.4. 7

The pharmacodynamic properties of the abovemen- The venous blood flowed into a rotameter and then tioned compounds were studied by the following meth- 30 over an oxygen electrode (a Beckman macroods:

I. TOXICITY The acute toxicity in mice was determined by the method of B. Behrens and C. Karber (Arclr.f.Erp.Path. Pharm, I77, 379( l935)).

The results obtained for the compounds set out in Table l are shown in Table 2 below.

electrode). The blood was returned to circulation through a catheter which was inserted into an external jugular and pushed very close to the auricular opening of the anterior vena cava. The arterial pressure was recorded at a carotid artery. Cardiographic electrodes were implanted in a D arrangement. The following parameters were recorded on a Beckman dynograph:

the coronary venous flow, the partial pressure of oxygen in the coronary venous blood,

the carotid arterial pressure, a D electrocardiogram for measuring the cardiac frequency, and

I the strength of the myocardium contractions measured by the ventricular gauge.

The results obtained with the compounds identified in Table l are given in Table 3 below, which shows ll. CARDlO-VASCULAR ACTION After being anaesthetized with chloralose (an 8% solution. l0 ml/kg I.V.), the test animal was tracheotomized and made to breath artificially; the chest was opened on the right after resection of the fifth rib. The pericardium was opened and a bridge strain gauge was sewn on the right ventricle. A hole was made in the right auricle, through which a catheter of the largest possible diameter was inserted into the coronary sinus and a transfixion point was placed in position and tightened around the auricular opening of the coronary sinus, in order to collect all the blood which flowed out. The animal was treated with heparin (830 units/kg).

their remarkable activity.

TABLE 3 Dose, Coro- Ventric- Cornmg./ nary Fre- Arterial ular pound kg. flow, quency, pressure, gauge, P01, 0. I.V. percent percent percent percent percent 4 150 128.2 123.8 18.2 1 126.25 5 T 77.2 1 10.8 1 15.4 1 28.8 T 103.2 5 T 107.6 1 21.2 23.2 1 19 1 187.4 5 64.2 1 9 15.8 1 14.4 T 129 5 84.1 1 21.5 25.1 T 10.8 T 115.7 5 .T 56 l 22 .l 17.8 1 14 T 192 5 T 9 l 15 l 2 5 T 33 17 14 T 18 5 I 58 14 1 6 T 7 5 T 17 6 T 6 i 5 T 18 T 16 T 19 T 16 l, 5 T 112 T s 35 t 46 1 143 5 1 32 i 15 T 5 t 24 T 115 5 T 42 31 1 24 l 27 T 96 TEST NOT EFFECTEI) 5 1 55 i J, an t 35 1 1m 17-.. 5 T 37 47 l 32 I 18.-- 5 T 56 T3 5 17 27 *Unmotililed. nmeasurahle.

A. Study of the spontaneous mobility of the mouse (Openfield test) Procedure.

Male animals having a weight of from 17 to 20g were divided into groups of 10 and received, by oesophageal intubation, after fasting for 2 hours, the compound to be tested (treated animals) or an equivalent quantity of the solvent used (control animals).

One hour after the administration of the compound or the solvent, the animals were placed in groups of two in a circular passage. The latter was swept by six beams of infra-red light. The beams were radially directed, equidistant and each centred on a photo-electric cell.

Each breaking of a beam caused by the passage of an orally. groups of l male mice weighing from 22 to 26 g. were subjected to a supramaximal electric shock (square current of constant intensity: 50 milliamps. 4O cycles/second. 10 milliseconds over a period of 0.2 seconds by means of corneal electrodes). The presence or the absence of tonic extension and its duration, and of clonic convulsions and their duration, were noted. The results are expressed as percentage protection against tonic extension with respect to a group of control animals.

Fifteen minutes later, the same mice received subcutaneously 1.5 mg/kg of strychnine sulphate, a convulsant poison of predominantly medullar action. The number of animals which did not die during the 60 minutes following the injection of strychnine were noted.

The results obtained are shown in Table 4 below.

Table 4 v Compound Action against Action against Action against No. mobility lethal dose of supramaximal (DosczBOmg/kg protection Dose( mg/kg) Z protection per os) (Dosc250mg/kg per 0s per os) 1 1 23% 0 400 0 2 TEST NOT TEST NOT EFFECTED EFFECTED 3 +175 0 TEST NOT EFFECTED 4 t 14% 0 1000 0 5 1 0 1000 6 t 12% o 250 0 7 1 80% 45% 50 50% 8 1 43% 100% 20% 40% 9 1 22% 85% 80% 10 70% 0 100 90% 1 1 1- 112% 0 100 0 12 t 60% 50% 25 13 t 61% 0 300 14 t 56% 50% 50 70% 1s 1 53% 0 250 0 l6 t 54% 0 300 0 17 64% 0 300 0 18 ED 50 omglkg 100 (ED 50 20 54% per os 17 mg/kg per animal was recorded on a counter. The number of IV. BACTERlOSTATlC ACTIVITY breaks, and therefore of movements of the two animals, Procedure. was taken at the end of 10 minutes. The results ob- The study was carried out by the dilution method in tained with the treated animals were expressed in the liquid medium (variable volume dilution method). The form of a percentage increase or reduction with respect medium used was the standard broth for the study of to those obtained with the controls. 50 antibiotics (Institut Pasteur of Paris, Cassagne 1961). B. Study on protection against a lethal dose of car- Dilutions of the compounds to be tested were added to diazol the medium to obtain final concentrations ranging step- Groups of 10 male mice having an averagee weight wise from 10 to 500 Lg/ml. These dilutions were obof 23 g received orally the compound to be tested (or, tained in distilled water from a mother solution in ethin the case of the controls, the equivalent weight of the ylene glycol. physiological solvent used) and 30 minutes afterwards, The test bacteria used were a strain of staphylococcus 100 mg/kg of cardiazol (pentetrazol), a convulsant of aureus Oxford A268 and of Escherichia coli 548 IP. The predominantly cortical action, were administered intratubes were inoculated with dilutions of a 24 hour culperitoneally to the animals. ture of the bacteria so as to obtain a final dilution of the The number of animals which did not die during the inoxulum of 10" for the staphylococcus and of 10" for 60 minutes following the injection of cardiazol were the Escherichia coli. The tubes were placed in an oven noted. maintained at 37C and examined after 24 hours and C. Protective action in mice with respect to supra- 48 hours. The minimum concentration which totally inmaximal electric shock and a lethal dose of strychnine. hibited the bacteria studied was noted (the minimum Procedure. One hour after receiving the compound to be tested inhibiting concentration, M.l.C., is expressed in ag/ml- Results:

Compound Staphylococcus Coli bacillus 3 4 30-100 pg/ml 500 pg/ml The compounds of formula I therefore appear to be suitable for the treatment of the following indications:

myocardic anoxia,

coronary insufficiency, angina,

myocardial infarctus, and

cardiac insufficiency linked with coronary circulation difficulties. They also have anti-convulsant and central nervous system stimulating activity.

For use in human or veterinary medicine, the compounds of formula I may be administered orally, rectally or parenterally. For oral administration, they may be formulated, for example, as compressed tablets, pastilles, capsules or granules; dosage units for oral administration preferably contain 0.250 g of the active compound.

For rectal administration, they may be formulated as in which Ar and Ar are phenyl, R is a lower alkyl group or phenyl, and A is 

